Medroxyprogesterone Acetate Impairs Amyloid Beta Degradation in a Matrix Metalloproteinase-9 Dependent Manner.

Keyana N Porter,Dominic D Quintana,Duaa A Dakhlallah,Mya E Vannoy,James W Simpkins,Saumyendra N Sarkar

doi:10.3389/fnagi.2020.00092

Abstract

Despite the extensive use of hormonal methods as either contraception or menopausal hormone therapy (HT), there is very little known about the potential effects of these compounds on the cellular processes of the brain. Medroxyprogesterone Acetate (MPA) is a progestogen used globally in the hormonal contraceptive, Depo Provera, by women in their reproductive prime and is a major compound found in HT formulations used by menopausal women. MPA promotes changes in the circulating levels of matrix metalloproteinases (MMPs), such as MMP-9, in the endometrium, yet limited literature studying the effects of MPA on neurons and astroglia cells has been conducted. Additionally, the dysregulation of MMPs has been implicated in the pathology of Alzheimer’s disease (AD), where inhibiting the secretion of MMP-9 from astroglia reduces the proteolytic degradation of amyloid-beta. Thus, we hypothesize that exposure to MPA disrupts proteolytic degradation of amyloid-beta through the downregulation of MMP-9 expression and subsequent secretion. To assess the effect of progestins on MMP-9 and amyloid-beta, in vitro, C6 rat glial cells were exposed to MPA for 48 h and then the enzymatic, secretory, and amyloid-beta degrading capacity of MMP-9 was assessed from the conditioned culture medium. We found that MPA treatment inhibited transcription of MMP-9, which resulted in a subsequent decrease in the production and secretion of MMP-9 protein, in part through the glucocorticoid receptor. Additionally, we investigated the consequences of amyloid beta-degrading activity and found that MPA treatment decreased proteolytic degradation of amyloid-beta. Our results suggest MPA suppresses amyloid-beta degradation in an MMP-9-dependent manner, in vitro, and potentially compromises the clearance of amyloid-beta in vivo.

Highlights

Alzheimer’s disease (AD) is a neurodegenerative disease with three key pathological hallmarks: the progressive accumulation of extracellular deposits; aggregates of intracellular protein; and loss of neurons and synapses
Accumulating evidence suggests matrix metalloproteinases (MMPs) secretion from astroglia contributes to the degradation and clearance of amyloid plaques (Yan et al, 2006; Yin et al, 2006; Wang et al, 2014), emphasizing the critical role of induction and secretion of MMPs in the brain
The present study investigated the expression of matrix metalloproteinase-9 (MMP-9) in C6 glial cells treated with Medroxyprogesterone Acetate (MPA)

Summary

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disease with three key pathological hallmarks: the progressive accumulation of extracellular deposits (amyloid plaques); aggregates of intracellular protein (neurofibrillary tangles); and loss of neurons and synapses (reviewed by Haass and Selkoe, 2007). As reviewed by Chen (2015), with aging, α-secretase becomes progressively inefficient. This causes APP to be truncated by non-specific proteases such as β-secretase and γ-secretase, promoting the amyloidogenic cleavage of APP (Holsinger et al, 2002; Yang et al, 2003; Zhang et al, 2014; Carroll and Li, 2016). Extracellular Aβ assumes several conformational states ranging from monomers to soluble oligomers and fibrils. These polymers of Aβ quickly aggregate and form the amyloid plaques which are characteristic of the disease (Pryor et al, 2012)

Objectives

Methods

Results

Conclusion